Control of sodium excretion by the kidneys is important in maintaining the correct amount of fluid and salt in the body. In some people, retention of salt and fluid causes hypertension. In others, it causes swelling of the legs, face, hands, abdomen (ascites), etc. Excess fluid can also collect in the lungs, causing difficulty in breathing.
Sodium and fluid retention can be caused by a number of different conditions or abnormalities, including heart, liver and kidney failure. Some patients retain fluid for reasons which are not entirely clear.
Numerous drugs which aid the kidneys in excreting fluid, referred to as diuretics, are currently available. These diuretics operate in different ways, and are suitable for different conditions. Some, such as the Loop of Henle diuretics (i.e., Furosemide, Ethacrynic Acid, and Bumetanide) (also called "high-ceiling" diuretics), operate by increasing the renal excretion of sodium (by inducing natriuresis), with increased fluid excretion following the increased sodium excretion. Such diuretics are among the few diuretics available that have an effect on patients with impaired renal function. See generally Goodman and Gilman's The Pharmacological Basis of Therapeutics 896-900 (A. G. Gilman, L. S. Goodman, T. W. Rall, and F. Murad 7th Ed. 1985) (hereinafter "Goodman and Gilman"); Veterinary Pharmacology and Therapeutics 492-98 (N. H. Booth and L. E. McDonald 5th Ed. 1982).
Diuretics are useful in veterinary medicine, as well as for treating humans. Animals treated with diuretics include, for example, dogs, cats, horses, and dairy cattle. These agents are administered to animals to treat edema, pulmonary congestion, ascites, hydrothorax, pulmonary edema, or any pathologic accumulation of noninflammatory fluid. Veterinary Pharmacology and Therapeutics, supra. In any case, all diuretics have undesirable side effects, and there is ongoing interest in developing new and better products in this field.
Because the control of sodium excretion is of such importance, there has been considerable interest in the identification of endogenous natriuretic factors which might play a role in physiology and pathophysiology. A number of endogenous natriuretic compounds have been identified. Chief among them are the prostaglandins, dopamine, fragments of the pro-opiomelanocortin molecule, and vasopressin. Recently, a family of peptides synthesized by the cardiac atria have been identified: these are referred to as atrial natriuretic factors. These peptides are released into the circulation following the ingestion of sodium, and appear to function as a natriuretic hormone. See also V. M. Buckalew and K. M. Gruber, Natriuretic Hormone, 46 Ann. Rev. Physiol. 343 (1984).
The possibility that a plasma lipid (or lipids) might function as a natriuretic hormone has only recently begun to emerge. Kelly et al., 260 J. Biol. Chem. 11,396 (1985), and Tamura et al., 26 J. Biol. Chem. 9672 (1985), have recently demonstrated that some of the digitalis-like activity in plasma is accounted for by a variety of lipids. Applicants' research into the mechanisms controlling sodium excretion has for the first time revealed that lysophospholipids are natriuretic.